The inflammatory process is a sequence of physiological events which can be elicited by numerous stimuli, including infectious agents, ischemia, antigen-antibody interactions, and thermal or other injurious insults. Although the sequence of events constituting an inflammatory reaction may vary according to the nature and location of the eliciting insult, there are certain events common to most inflammatory reactions. These include, in the acute phase, vasodilation, resulting in increased blood flow to the inflamed region and increased capillary permeability. This phase is followed by an increase in fluid in the region (edema) and movement of blood leukocytes and, finally, phagocytes from the blood vessels to the region.
It would be desirable, for treatment of inflamed tissues or regions, to target therapeutic compounds selectively to the region via the bloodstream. Site-specific targeting would be particularly helpful in reducing toxic side effects and in increasing the dose of drug which can safely be delivered to an inflamed region.
Liposomes have been proposed as a drug carrier for intravenously (IV) administered compounds, including both imaging and therapeutic compounds. However, the use of liposomes for site-specific targeting via the bloodstream has been severely restricted by the rapid clearance of liposomes by cells of the reticuloendothelial system (RES). Typically, the RES will remove 80-95% of a dose of IV injected liposomes within one hour, effectively outcompeting the selected target site for uptake of the liposomes.
A variety of factors which influence the rate of RES uptake of liposomes have been reported (e.g., Gregoriadis, 1974; Jonah; Gregoriadis, 1972; Juliano; Allen, 1983; Kimelberg, 1976; Richardson; Lopez-Berestein; Allen, 1981; Scherphof; Gregoriadis, 1980; Hwang; Patel, 1983; Senior, 1985; Allen, 1983; Ellens; Senior, 1982; Hwang; Ashwell; Hakomori; Karlsson; Schauer; Durocher; Greenberg; Woodruff; Czop; and Okada). Briefly, liposome size, charge, degree of lipid saturation, and surface moieties have all been implicated in liposome clearance by the RES. However, no single factor identified to date has been effective to provide long blood halflife, and more particularly, a relatively high percentage of liposomes in the bloodstream 24 hours after injection.
In addition to a long blood halflife, effective drug delivery to an inflamed site would also require that the liposomes be capable of penetrating the continuous endothelial cell layer and underlying basement membrane surrounding the vessels supplying blood to the region. A characteristic of local inflammation is a general, acute increase in permeability of the vasculature to proteins in the region of the inflammation, followed by migration of neutrophils out of the bloodstream into the inflamed region. However, neither of these events predicts the ability of liposomes to pass through the epithelial cell barriers and adjacent basement membrane, since proteins are generally much smaller than liposomes, and neutrophils possess specific binding sites and active mechanisms for penetrating the blood vessels.
In fact, studies reported to date indicate that even where the permeability of blood vessels increases, extravasation of conventional liposomes through the vessels does not increase significantly (Poste). Based on these findings, it was concluded that although extravasation of liposomes from capillaries compromised by disease may be occurring on a limited scale below detection levels, its therapeutic potential would be minimal (Poste).